Nephrogenic diabetes insipidus (NDI), a form of diabetes insipidus, is a disease characterized by the production of large quantities of dilute urine, which results from the inability of the kidney to respond to vasopressin, the primary hormone known to enable urine concentration. To avoid dehydration, those diagnosed with NDI must consume enough fluids to equal the amount of urine produced, which may be as high as 20 L of water per day. Some possible outcomes of the severe dehydration include low blood pressure, delirium, or mental retardation.
Vasopressin regulates urea transport through the activation of two cyclic AMP (cAMP) dependent signaling pathways: protein kinase A (PKA) and exchange protein activated by cAMP (Epac). Vasopressin acts by increasing the phosphorylation and apical plasma membrane accumulation of the UT-A1 urea transporter protein. Vasopressin has also been shown to regulate water transport via increasing phosphorylation and apical plasma membrane accumulation of the aquaporin-2 (AQP2) water channel. Thus, the inability of the kidney to respond to vasopressin manifests itself in irregularities in urine and water transport, leading to improper urine concentrations. See FIG. 1. See Sands et al., Epac regulation of the UT-A1 urea transporter in rat IMCDs, J Am Soc Nephrol, 20: 2018-2024, 2009 and Sands et al., Urea transport in the kidney, Compr Physiol, 1: 699-729, 2011.
Aside from lifestyle modifications that include increased water consumption and changes in diet, hydrochlorothiazide and amiloride are diuretics that manage the dehydration associated with NDI. Currently, there exist no therapies specifically targeted towards NDI. Therefore, there is a need for therapeutic treatments that address the kidney function in NDI cases.
A website reports studies entitled “How effective is Metformin hydrochloride for Diabetes insipidus?” 2013, available at http://www.ehealthme.com/ed/diabetes+insipidus/metformin+hydrochloride. Metformin has been used as a type II diabetes medication. See WO2012156298A1, EP2324853A1, EP2329848A1.
References cited herein are not an admission of prior art.